JP5787764B2 - ジヒドロエトルフィンおよびその調製 - Google Patents
ジヒドロエトルフィンおよびその調製 Download PDFInfo
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- JP5787764B2 JP5787764B2 JP2011539101A JP2011539101A JP5787764B2 JP 5787764 B2 JP5787764 B2 JP 5787764B2 JP 2011539101 A JP2011539101 A JP 2011539101A JP 2011539101 A JP2011539101 A JP 2011539101A JP 5787764 B2 JP5787764 B2 JP 5787764B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems
- C07D489/10—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems
- C07D489/10—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14
- C07D489/12—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14 the bridge containing only two carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Emergency Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
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|---|---|---|---|
| GB0822342A GB0822342D0 (en) | 2008-12-08 | 2008-12-08 | Dihydroetorphine |
| GB0822342.2 | 2008-12-08 | ||
| GB0920699A GB0920699D0 (en) | 2009-11-26 | 2009-11-26 | Dihydroetorphine |
| GB0920699.6 | 2009-11-26 | ||
| PCT/GB2009/051655 WO2010067101A1 (en) | 2008-12-08 | 2009-12-04 | Dihydroetorphines and their preparation |
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| JP2015116455A Division JP6151307B2 (ja) | 2008-12-08 | 2015-06-09 | ジヒドロエトルフィンおよびその調製 |
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Cited By (1)
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| JP2015157864A (ja) * | 2008-12-08 | 2015-09-03 | ユーロ−セルティーク エス．エイ． | ジヒドロエトルフィンおよびその調製 |
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| EP2941433B1 (en) | 2012-12-31 | 2019-08-07 | Rhodes Technologies | Process for preparing 7 -substituted 6 ,14 -ethenomorphinans and 7 -substituted 6 ,14 -ethanomorphinans |
| GB201309654D0 (en) | 2013-05-30 | 2013-07-17 | Euro Celtique Sa | Method |
| EP3023427A1 (en) * | 2014-11-19 | 2016-05-25 | Siegfried AG | Improved method of manufacturing buprenorphine and analogues thereof from oripavine |
| EP3067357A1 (en) * | 2015-03-11 | 2016-09-14 | Siegfried AG | Method of manufacturing stereoisomers of buprenorphine and analogues thereof |
| GB201513441D0 (en) * | 2015-07-30 | 2015-09-16 | Euro Celtique Sa | Transdermal delivery system |
| GB201513442D0 (en) * | 2015-07-30 | 2015-09-16 | Euro Celtique Sa | Transdermal patch |
| CN114105875B (zh) * | 2021-12-06 | 2023-11-03 | 四川大学 | 一种吗啡衍生物二氢埃托啡的合成方法 |
| EP4613751A1 (en) | 2024-03-07 | 2025-09-10 | Siegfried AG | Method of making chemical compounds useful for the synthesis of buprenorphine |
Family Cites Families (67)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB925723A (en) | 1960-09-05 | 1963-05-08 | J F Macfarlan & Company Ltd | Novel thebaine derivatives |
| GB937214A (en) | 1961-06-02 | 1963-09-18 | J F Macfarlan & Company Ltd | Oripavine derivatives |
| JPS59184182A (ja) | 1983-04-02 | 1984-10-19 | Res Inst For Prod Dev | ３−ベンゾイルチオ−４、５α−エポキシ−７α−〔１（Ｒ）−ヒドロキシ−１−メチルベンチル〕−６−メトキシ−１７−メチル−６、１４−エンド−エタノモルヒナン |
| JPS62153214A (ja) | 1985-12-26 | 1987-07-08 | Nitto Electric Ind Co Ltd | 医薬製剤 |
| JPS62281815A (ja) | 1986-05-27 | 1987-12-07 | Teisan Seiyaku Kk | 貼付剤及びその製造法 |
| JPS63201119A (ja) | 1987-02-17 | 1988-08-19 | Kao Corp | 貼付剤組成物 |
| US4891377A (en) | 1988-12-02 | 1990-01-02 | Board Of Regents Acting For And On Behalf Of University Of Michigan | Transdermal delivery of the narcotic analgesics etorphine and analogs |
| PT95069B (pt) | 1989-08-24 | 1997-10-31 | Searle & Co | Processo para a preparacao de (+)-isomeros de derivados de endoetano/endoetanoepoximofinano, uteis como agentes anti-tussicos |
| US5271940A (en) | 1989-09-14 | 1993-12-21 | Cygnus Therapeutic Systems | Transdermal delivery device having delayed onset |
| US5633259A (en) | 1992-09-21 | 1997-05-27 | United Biomedical, Inc. | Method for identification of low/non-addictive opioid analgesics and the use of said analgesics for treatment of opioid addiction |
| EP0668764A1 (en) | 1992-09-21 | 1995-08-30 | QIN, Bo-yi | Methods for identifying and using low/non-addictive opioid analgesics |
| JP2819236B2 (ja) | 1994-05-06 | 1998-10-30 | 日東電工株式会社 | 経皮吸収製剤 |
| UA48973C2 (uk) | 1995-06-07 | 2002-09-16 | Орто-Макнейл Фармасьютікалз Інк. | Трансдермальний пластир на основі 17-деацетилноргестимату для попередження овуляції |
| AUPN603895A0 (en) | 1995-10-19 | 1995-11-09 | University Of Queensland, The | Production of analgesic synergy by co-administration of sub-analgesic doses of two strong opioids |
| US6103258A (en) | 1996-04-12 | 2000-08-15 | Simon; David Lew | Salts and bases of the 17-(Cyclopropylmethyl)-4,5 alpha-epoxy-6-Methylenemorphinan-3,14 diol molecule for optimizing dopamine homeostasis during administration of opioid analgesics |
| KR100204659B1 (ko) * | 1996-05-28 | 1999-06-15 | 강재헌 | 신규한 부프레노핀계 진통제용 화합물 |
| JPH10231248A (ja) | 1997-02-19 | 1998-09-02 | T T S Gijutsu Kenkyusho:Kk | ジヒドロエトルフィン含有経皮吸収型製剤 |
| SI1039882T1 (sl) | 1998-08-27 | 2011-01-31 | Pfizer Health Ab | Terapevtska formulacija za dajanje tolterodina s kontroliranim sproščanjem |
| US6194382B1 (en) * | 1999-03-03 | 2001-02-27 | Albert Einstein College Of Medicine Of Yeshiva University | Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists |
| US6765010B2 (en) | 1999-05-06 | 2004-07-20 | Pain Therapeutics, Inc. | Compositions and methods for enhancing analgesic potency of tramadol and attenuating its adverse side effects |
| US6312716B1 (en) | 1999-05-10 | 2001-11-06 | Peierce Management Llc | Patch and method for transdermal delivery of bupropion base |
| US6716449B2 (en) | 2000-02-08 | 2004-04-06 | Euro-Celtique S.A. | Controlled-release compositions containing opioid agonist and antagonist |
| JP4659943B2 (ja) * | 2000-02-25 | 2011-03-30 | 帝三製薬株式会社 | 塩酸ブプレノルフィン含有貼付剤 |
| CN1438861A (zh) | 2000-04-26 | 2003-08-27 | 沃特森药物公司 | 最小化与奥昔布宁疗法有关的副作用 |
| US6372252B1 (en) | 2000-04-28 | 2002-04-16 | Adams Laboratories, Inc. | Guaifenesin sustained release formulation and tablets |
| MXPA02003670A (es) | 2000-07-13 | 2003-01-28 | Euro Celtique Sa | Sales y bases de 17-(ciclopropilmetil)-4,5 alfa-epoxi-6-metilenomorfinan-3,14 diol para optimizar la homeostasis de dopamina durante la administracion de analgesicos. |
| US7141250B2 (en) | 2001-08-06 | 2006-11-28 | Euro-Celtique S.A. | Pharmaceutical formulation containing bittering agent |
| US7332182B2 (en) | 2001-08-06 | 2008-02-19 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant |
| ATE341552T1 (de) | 2001-08-10 | 2006-10-15 | Neuro Therapeutics Ltd | Derivate morphinähnlicher opioidverbindungen |
| CN1233645C (zh) * | 2001-09-14 | 2005-12-28 | 中国人民解放军军事医学科学院毒物药物研究所 | 新的东罂粟碱衍生物及其医药用途 |
| EP1476155A4 (en) | 2002-01-23 | 2009-10-28 | Univ California | METHODS AND COMPOSITIONS FOR REDUCING THE DEVELOPMENT OF DRUG TOLERANCE AND / OR PHYSICAL DEPENDENCE |
| US20060177381A1 (en) | 2002-02-15 | 2006-08-10 | Howard Brooks-Korn | Opiopathies |
| US20040033253A1 (en) | 2002-02-19 | 2004-02-19 | Ihor Shevchuk | Acyl opioid antagonists |
| US20030191147A1 (en) | 2002-04-09 | 2003-10-09 | Barry Sherman | Opioid antagonist compositions and dosage forms |
| CN1655772B (zh) | 2002-05-28 | 2010-05-26 | 拉伯泰克技术研发有限公司 | 含有芬太尼的贴剂 |
| SI1513532T1 (sl) | 2002-06-10 | 2007-08-31 | Euro Celtique Sa | Sistemi za odstranjevanje priprav za transdermalno oddajanje za preprečevanje zlorabe učinkovin, ki jih vsebujejo |
| WO2004017941A2 (en) | 2002-08-20 | 2004-03-04 | Euro-Celtique, S.A. | Transdermal dosage form comprising an active agent and a salt and free-baseform of an antagonist |
| AU2002951965A0 (en) | 2002-10-09 | 2002-10-24 | Monash University | Amidine compounds |
| TWI296531B (en) | 2002-10-18 | 2008-05-11 | Hisamitsu Pharmaceutical Co | Transdermal adhesive preparations for topical administration of fentanyl |
| TW200500067A (en) | 2003-01-21 | 2005-01-01 | Control Delivery Sys Inc | Salts of codrugs and uses related thereto |
| US20040208917A1 (en) | 2003-04-16 | 2004-10-21 | Wilfried Fischer | Transdermal systems for the release of clonidine |
| MY141815A (en) | 2003-04-30 | 2010-06-30 | Purdue Pharma Lp | Tamper-resistant transdermal dosage form comprising an active agent component and an adverse agent component at the distal site of the active agent layer |
| US20050113365A1 (en) | 2003-11-10 | 2005-05-26 | Sir Isaac Newton Enterprises Llc | Method and medicine for treating gastrointestinal disorder including irritable bowel syndrome |
| CN100500151C (zh) | 2004-04-02 | 2009-06-17 | 北京万全阳光医药科技有限公司 | 一种水溶性药物舌下给药制剂 |
| WO2005112926A1 (en) | 2004-05-17 | 2005-12-01 | Pharmacofore, Inc. | Compositions and methods for treating or preventing pain |
| AU2006235318A1 (en) | 2005-04-07 | 2006-10-19 | Hythiam, Inc. | Improved methods of and compositions for the prevention of anxiety, substance abuse, and dependence |
| EP1868664A2 (en) | 2005-04-15 | 2007-12-26 | Interface Biologics Inc. | Methods and compositions for the delivery of biologically active agents |
| KR100764679B1 (ko) | 2005-07-22 | 2007-10-09 | 익수제약 주식회사 | 파록세틴을 함유하는 경피투여용 패취제 |
| EP1928881A2 (en) | 2005-08-19 | 2008-06-11 | Pharmacofore, Inc. | Prodrugs of active agents |
| WO2007052308A2 (en) | 2005-11-03 | 2007-05-10 | Brain N' Beyond Biotech Pvt. Ltd. | Glyco-phosphorylated biologically active agents |
| GB0523031D0 (en) | 2005-11-11 | 2005-12-21 | Yaupon Therapeutics | Enhancement of morphine analgesia by s(-)-norketamine |
| TWI389709B (zh) | 2005-12-01 | 2013-03-21 | Novartis Ag | 經皮治療系統 |
| US8071125B2 (en) | 2005-12-09 | 2011-12-06 | Beijing Kangbeide Pharmaceutical Technology Development Co., Ltd. | Transdermal patch containing isosorbide dinitrate and bisoprolol |
| JP2009530307A (ja) | 2006-03-15 | 2009-08-27 | アルザ コーポレイション | 骨減少症を予防し、または治療するための副甲状腺ホルモン薬の経皮送達のための装置、並びに方法 |
| USD576282S1 (en) | 2006-06-16 | 2008-09-02 | Activatek, Inc. | Adhesive transdermal medicament patch |
| USD625017S1 (en) | 2006-08-11 | 2010-10-05 | Hisamitsu Pharmaceutical Co., Inc. | Medical transdermal patch |
| DE102006050558B4 (de) | 2006-10-26 | 2009-03-26 | Lts Lohmann Therapie-Systeme Ag | Transdermales therapeutisches System enthaltend Norelgestromin zur Kontrazeption und Hormonsubstitution |
| CN100512817C (zh) | 2006-11-15 | 2009-07-15 | 闫章年 | 复方噻拉嗪注射液及制备工艺 |
| DE102006054731B4 (de) * | 2006-11-21 | 2013-02-28 | Lts Lohmann Therapie-Systeme Ag | Transdermales therapeutisches System zur Verabreichung des Wirkstoffs Buprenorphin und Verwendung desselben in der Schmerztherapie |
| WO2008083149A1 (en) | 2006-12-27 | 2008-07-10 | Abeille Pharmaceuticals Inc. | Transdermal method and patch for corticosteroid administration |
| PL2137189T3 (pl) * | 2007-03-06 | 2015-12-31 | SpecGx LLC | Sposób wytwarzania czwartorzędowych N-alkilowych soli alkaloidu morfinanowego |
| CN101147739B (zh) | 2007-07-06 | 2010-12-08 | 北京康倍得医药技术开发有限公司 | 含罗替戈汀的组合物及其制药用途以及含该组合物的透皮贴剂 |
| KR100929560B1 (ko) | 2008-01-09 | 2009-12-03 | 에코 퍼시픽 엘티디 | 그라니세트론을 함유한 매트릭스 형태의 경피 흡수제 |
| EP2286814B1 (en) | 2008-05-15 | 2013-10-16 | Hisamitsu Pharmaceutical Co., Inc. | Transdermal preparation containing palonosetron |
| TWI630208B (zh) | 2008-12-08 | 2018-07-21 | 歐陸斯迪公司 | 二氫羥戊甲嗎啡 |
| EP2298277A1 (en) | 2009-09-09 | 2011-03-23 | Labtec GmbH | Transdermal patch formulation |
| DE102010040299A1 (de) | 2010-09-06 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Transdermale therapeutische Systeme mit kristallisationsinhibierender Schutzfolie (Release Liner) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2015157864A (ja) * | 2008-12-08 | 2015-09-03 | ユーロ−セルティーク エス．エイ． | ジヒドロエトルフィンおよびその調製 |
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